The present invention relates to a method for preparing heterocyclic carboxylic acid compounds, especially quinoxaline-5- and 6-carboxylic acids.
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience; are numerically referenced in the following text and respectively grouped in the appended bibliography.
Quinoxaline-6-carboxylic acid is an important chemical intermediate for the preparation of compounds such as AMPHAKINE CX516(copyright) [1-(quinoxalin-6-ylcarbonyl)piperidine], a drug being tested for the treatment of Alzheimer""s disease, Attention Deficit Hyperactivity Disorder (ADHD), Mild Cognitive Impairment (MCI), Chronic Schizophrenia and male sexual dysfunction (1). The preparation of AMPHAKINE CX516(copyright) involves the conversion of 3,4-diaminobenzoic acid to quinoxaline-6-carboxylic acid with sodium glyoxal bisulfite, followed by amidation of the resulting acid with piperidine, as set out below (2, 12). 
Although the preparation of AMPHAKINE CX516(copyright) appears straightforward, the synthesis requires the use of 3,4-diaminobenzoic acid, an expensive starting material. For example, preparation of the isomeric 2,3-diaminobenzoic acid employs a multi-step method that includes oxidation, reduction, amidation, nitration, separation of isomers, further reduction, and hydrolysis, as set out below (3). Preparation of the isomeric 3,4-diaminobenzoic acid can be carried out using this multi-step method by isolating and further reacting the 3-amido, 4-nitrobenzoic acid isomer. 
Other methods for preparing 3,4-diaminobenzoic-acid involve the electrochemical reduction of 3,4-dinitrobenzoic acid and the hydrogenation of substituted benzofurazans (4). These methods also employ expensive chemical intermediates.
Initial attempts by the applicant to prepare quinoxaline-6-carboxylic acid focused on a one step selective oxidation of the benzyl group to a carboxylic acid without affecting the aromatic rings, as set out below. 
Many methods are known for the direct oxidation of benzylic methyl groups to carboxylic acids. These methods typically employ a strong oxidizing agent, such as potassium permanganate, that reacts with a methyl group providing the remainder of the molecule is not reactive to the oxidizing agent (5). Thus, toluene can be oxidized with potassium permanganate to benzoic acid without affecting the benzene ring (5). Catalytic methods are generally more acceptable for industrial scale because theses methods employ milder oxidizing agents, i.e., air or oxygen, to carry out the oxidation of benzylic methyl groups to the corresponding carboxylic acid (6). The oxidation of 5- and 6-methyl-quinoxalines to 5- and 6-quinoxaline-carboxylic acids is not so straightforward, however, because strong oxidizing agents, such as potassium permanganate, degrade the aromatic ring yielding 2,3-pyrazinedicarboxylic acid (7): 
Milder oxidizing agents, i.e., air or oxygen in the presence of a catalyst, on the other hand, have no effect on the benzylic methyl group of 5- or 6-methyl-quinoxaline. Air in the presence of a cobalt salt can oxidize toluene to benzoic acid (6) but does not oxidize methyl-quinoxaline to quinoxaline-carboxylic acid. Similarly, air and oxygen in the presence of a palladium or platinum catalyst are also ineffective (8). Most known oxidizing reagents are either too mild to react with methyl-quinoxalines or are too reactive causing structural changes. 
Because attempts to prepare quinoxaline-6-carboxylic acid via a one-step selective oxidation of the benzyl group were not successful, a two-step method to prepare quinoxaline-6-carboxylic acid was developed. In the first step, 6-methyl-quinoxaline is halogenated to provide a 6-halomethyl-quinoxaline intermediate. In the second step, the 6-halomethyl-quinoxaline intermediate is oxidized to the corresponding quinoxaline-6-carboxylic acid.
The present invention pertains to a method for preparing quinoxaline-5- and 6-carboxylic acids (I) which comprises contacting an aqueous alkaline suspension of a 5- or 6-halomethyl quinoxaline (II) with oxygen in the presence of a transition metal catalyst, to form the respective quinoxaline-5- or 6-carboxylic acid (I), wherein X is halogen. 
The present invention also pertains to a method for preparing a carboxylic acid selected from the group consisting of: 
The method comprises contacting an aqueous alkaline suspension of a halomethyl precursor compound of the respective carboxylic acid with oxygen in the presence of a transition metal catalyst, to form the respective carboxylic acid.
The present invention pertains to a two-step method for converting benzyl heterocyclic compounds to the corresponding carboxylic acid heterocyclic compounds. The two-step method is especially suitable for converting 5- and 6-benzyl quinoxalines to the corresponding quinoxaline-5- and 6-carboxylic acids. The 5- and 6-benzyl quinoxalines may be prepared from ortho-diaminotoluenes, such as 2,3- and 3,4-diaminotoluene, by condensation with sodium glyoxal bisulfite. The method for oxidizing benzylic methyl groups may also be employed to prepare a wide variety of heterocyclic carboxylic acid compounds.
In the first step, 6-methyl-quinoxaline is halogenated to provide a 6-halomethyl-quinoxaline intermediate. 
This first step is more fully described in copending patent application Ser. No. 09/909,000, now U.S. Pat. No. 6,492,517, entitled xe2x80x9cMethod For Preparing Halomethyl Heterocyclic Compoundsxe2x80x9d filed by applicant on Jul. 19, 2001 concurrently with the present patent application, and assigned to the assignee of this application, which is hereby incorporated by reference.
In the second step, the 6-halomethyl-quinoxaline intermediate is oxidized to the corresponding quinoxaline-6-carboxylic acid. 
As set out above, 5- and 6-benzyl quinoxalines may be prepared from ortho-diaminotoluenes, such as 2,3- and 3,4-diaminotoluene, by condensation with sodium glyoxal bisulfite. For example, 6-benzyl quinoxaline may be prepared by condensation of 3,4-diaminotoluene with sodium glyoxal bisulfite (9).
Because attempts to prepare quinoxaline-6-carboxylic acid via a one-step selective oxidation of the benzyl group were not successful, a two-step method to prepare quinoxaline-6-carboxylic acid was developed. In the first step, 6-methyl-quinoxaline is halogenated to provide a 6-halomethyl-quinoxaline intermediate. In the second step, the 6-halomethyl-quinoxaline intermediate is oxidized to the corresponding quinoxaline-6-carboxylic acid.
In the first step of the synthesis, a benzylic methyl heterocyclic compound and a halogenating agent, such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), are reacted in the presence of a radical initiator, such as benzoyl peroxide or azobisisobutyronitrile, in a suitable solvent, to form the respective halomethyl heterocyclic compound, such as 5- or 6-halomethyl quinoxaline (I). Suitable solvents may be selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1,xcex1,xcex1-trifluorotoluene and xcex1,xcex1,xcex1-trichlorotoluene.
The method for halogenating benzylic positions may also be employed to halogenate a variety of heterocyclic compounds. The method typically affords good yields of halomethyl-quinoxalines when [6QX]/[benzoyl peroxide]xe2x89xa640 while maintaining a temperature in the range of 60xc2x0 C. to 115xc2x0 C. for a period of 1 to 12 hours. Yields for benzylic brominations (conversions xe2x89xa795%, selectivities xe2x89xa797%) are in general better than for benzylic chlorinations (conversions 60%, selectivities xcx9c75-80%). The 5- or 6-halomethyl quinoxaline may be a 5-halomethyl quinoxaline or may be a 6-halomethyl quinoxaline. The halomethyl may be a chloromethyl or may be a bromomethyl.
The method comprises contacting the benzyl precursor compound of the respective halomethyl compound with a halogenating agent in the presence of a radical initiator in a solvent selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1,xcex1,xcex1-trifluorotoluene and xcex1,xcex1,xcex1-trichlorotoluene, to form the respective halomethyl compound.
The benzylic halogenation of heterocyclic compounds, such as methyl-quinoxalines, depends on a variety of factors including the halogenating agent, the radical initiator, the solvent, temperature, reaction time, reagent concentrations, and procedure.
The halogenating agents which may be employed in the present invention may be any halogenating agent which is capable of selectively halogenating the benzylic methyl group of a heterocyclic compound. The term xe2x80x9chalogenxe2x80x9d, as used herein, refers to the elements fluorine, chlorine, bromine, and iodine. Preferred halogens are chlorine and bromine. Non-limiting illustrative halogenating agents may be selected from the group consisting of N-chlorosuccinimide, N-bromosuccinimide, Cl2, Br2, t-butyl hypochlorite, N-chloroglutarimide, N-bromoglytarimide, N-chloro-N-cyclohexyl-benzenesulfonimide, and N-bromophthalimide. Preferred halogenating agents are N-chlorosuccinimide and N-bromosuccinimide.
The radical initiators which may be employed in the present invention may be any radical initiator which is capable of catalyzing the halogenating agent to selectively halogenate the benzylic methyl group of a heterocyclic compound. The presence of an initiator is essential for the reaction to occur because radicals propagate these reactions. Non-limiting illustrative radical initiator agents may be selected from the group consisting of benzoyl peroxide, azobisisobutyronitrile (AIBN), and diacyl peroxides, dialkyl peroxydicarbonates, and tert-alkylperoxyesters, monoperoxycarbonates, di(tert-alkylperoxy)ketals, ketone peroxides. Preferred radical initiators are benzoyl peroxide and azobisisobutyronitrile. Alternatively, radicals can be generated photochemically.
The solvents which may be employed in the present invention may be any solvent which is capable of promoting the halogenating agent to selectively halogenate the benzylic methyl group of a heterocyclic compound. The choice of solvent is critical. The solvent must (a) be a media in which the halogenating agent has a low, but definite, solubility; (b) be stable to the halogenating agent allowing the halogenating agent to react preferentially at the methyl group of the heterocyclic compound to provide a halomethyl-heterocyclic compound that is stable in the solvent under the reaction conditions; and (c) be environmentally acceptable. Most conventional benzylic bromination procedures employ highly toxic solvents which are rigorously restricted on an industrial level. Suitable solvents may be selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1,xcex1,xcex1-trifluorotoluene and xcex1,xcex1,xcex1-trichlorotoluene. Preferred solvents are chlorobenzene and xcex1,xcex1,xcex1-trifluorotoluene.
In the second step of the synthesis, an aqueous alkaline suspension of a 5- or 6-halomethyl quinoxaline (II) is contacted with oxygen in the presence of a transition metal catalyst, to form the respective quinoxaline-5- or 6-carboxylic acid (I). X is halogen. 
The method for oxidizing benzylic methyl groups may also be employed to prepare a wide variety of heterocyclic carboxylic acid compounds.
In one preferred embodiment, the invention is directed to a method for preparing quinoxaline-5- and 6-carboxylic acids (I). The method comprises contacting an aqueous alkaline suspension of a 5- or 6-halomethyl quinoxaline (II) with oxygen in the presence of a transition metal catalyst, to form the respective quinoxaline-5- or 6-carboxylic acid (I). X is halogen. 
In another preferred embodiment, the invention is directed to a method for preparing a carboxylic acid selected from the group consisting of: 
The method comprises contacting an aqueous alkaline suspension of a halomethyl precursor compound of the respective carboxylic acid with oxygen in the presence of a transition metal catalyst, to form the respective carboxylic acid.
The method for oxidizing benzylic halomethyl compounds, such as halomethyl-quinoxalines, depends on a variety of factors including the aqueous alkaline suspension, the source of oxygen, the transition metal catalyst, temperature, reaction time, reagent concentrations, and procedure.
The aqueous alkaline suspension which may be employed in the present invention may be any aqueous alkaline suspension of a 5- or 6-halomethyl quinoxaline (II) having a pH value which is capable of selectively oxidizing the benzylic halomethyl group of a heterocyclic compound. Preferably, the aqueous alkaline suspension of a 5- or 6-halomethyl quinoxaline (II) may have a pH value in the range from about 7 to about 14, preferably from about 8 to about 14, and more preferably from about 12 to about 14. Suitable sources for providing the alkalinity include alkali and alkaline earth metal oxides, hydroxides, carbonates, and tetraalkylammonium hydroxide salts.
The source of oxygen which may be employed in the present invention may be any source of oxygen which is capable of selectively oxidizing the benzylic halomethyl group of a heterocyclic compound. Oxygen, air, and mixtures thereof may be employed.
The transition metal catalysts which may be employed in the present invention may be any catalyst which is capable of selectively catalyzing the oxidation of the benzylic halomethyl group of a heterocyclic compound. Non-limiting illustrative transition metal catalysts may be selected from the group consisting of Pd, Pt, Ru, Co, Mn, Cu, and V, especially on supports such as carbon, alumina, silica, and titania. Preferably, the transition metal catalyst is Pd/C or Pt/C.
The temperatures which may be employed in the method for preparing quinoxaline-5- and 6-carboxylic acids of the present invention are important to ensure that the benzylic group is oxidized. The temperature should be chosen so that an optimum reaction rate can be reached. Such temperatures may range from about 50xc2x0 C. to about 150xc2x0 C., preferably from about 80xc2x0 C. to about 120xc2x0 C.
The reaction times which may be employed in the present invention play an important role in the method for preparing quinoxaline-5- and 6-carboxylic acids. Thus, reaction times should be optimum to ensure maximum conversion. Suitable reaction times may range from about 4 to about 72 hours, preferably from about 8 to about 48 hours.
The reagent concentrations which may be employed in the present invention should be optimum to ensure maximum conversion. The quinoxaline concentrations may range from about 0.05M to about 0.5M, preferably from about 0.1M to about 0.3M. The alkali concentration may range from about 0.5M to about 3M, preferably from about 0.9M to about 1.5M.
The method of the present invention has been used for the synthesis of quinoxaline-6-carboxylic acid, a precursor for AMPHAKINE CX516(copyright) (I), but other carboxylic acids may also be prepared by the methods of the present invention. In particular, substrates that are fragile towards strong oxidants but are impervious towards mild oxidizing agents (i.e. quinolines, triazoles, ureas derived from ortho-diaminotoluenes, etc) can be oxidized to their corresponding acids. Examples of carboxylic acids that can be made by the present method are: 
After oxidation of the halomethyl-quinoxaline, the product can remain in the aqueous solution as a salt of the quinoxaline-carboxylic acid (i.e., sodium 6-quinoxaline carboxylate). The resulting aqueous solution can then be extracted if necessary with ether (to remove any remaining organic contaminant) followed by acidification with a mineral acid. The pale yellow solid that precipitates (i.e. 6-quinoxaline carboxylic acid) can be filtered, washed with water, and air-dried (xcx9c80% yield). The typical yield for the first step (halomethyl-quinoxaline synthesis) is 97% selectivity and 95% conversion. The typical yield for the second step (oxidation step) is xcx9c80%.
All attempts by applicant to prepare quinoxaline-6-carboxylic acid directly from 6-methyl-quinoxaline failed (i.e., without making the halomethyl-quinoxaline intermediate). These attempts included air oxidation with cobalt catalyst in acetic acid; air oxidation with Co/Mn/Clxe2x80x94/Brxe2x88x92 catalyst in acetic acid; air oxidation with 5% Pd/C catalyst; KMnO4; KCrO4; and ruthenium catalyst in the presence of sodium hypochlorite.
There are several advantages in using the present method compared to conventional methods. The present method is simple because the new method can convert a readily available chemical (2,3- or 3,4-diaminotoluene) into a valuable pharmaceutical intermediate in only three steps. Also, the method requires only routine operations (filtrations, distillation, extraction, etc) without the need to employ complex chemical operations or purification procedures. The present method is also economical because the method does not use exotic chemicals and it can produce the desire product in a good yield. Also, using catalytic air oxidation creates fewer environmental problems typically associated with oxidation procedures that rely on metal-oxo compounds (i.e., potassium permanganate). Because the new method takes advantage of diaminotoluenes as a raw material, the synthesis of 6-quinoxaline-carboxylic acid is less laborious and more economical.
Throughout this disclosure, applicant will suggest various theories or mechanisms by which applicant believes the present methods function. While applicant may offer various mechanisms to explain the present invention, applicant does not wish to be bound by theory. These theories are suggested to better understand the present invention but are not intended to limit the effective scope of the claims.